HYPOXIC ISCHAEMIC

ENCEPHALOPATHY

Dr. Mohit Goel, JRIII

Department of Radiodiagnosis

Bharati Vidyapeeth University, Pune

19/05/2014

INTRODUCTION

Hypoxic-ischemic injury (HII) to the brain is a devastating occurrence that

frequently results in death or profound long-term neurologic disability in

both children and adults.

Imaging findings in HII are highly variable and depend on a number of

factors, including brain maturity, severity and duration of insult, and type

and timing of imaging studies.

PATHOPHYSIOLOGY

Regardless of the specific cause of injury, the common underlying

physiologic processes that result in HII are diminished cerebral blood

flow (ischemia) and reduced blood oxygenation (hypoxemia).

In general, infants and children are more likely to suffer asphyxial

events, which result in hypoxemia and brain hypoxia.

With prolonged hypoxemia, cardiac hypoxia occurs, leading to

diminished cardiac output and, ultimately, to brain ischemia.

PATHOPHYSIOLOGY

Adults more frequently suffer brain ischemia as a result of cardiac

arrest or cerebrovascular disease, with secondary hypoxia due to

reduced blood flow.

From the model just described, we can draw the following

conclusions:

(a) the areas of the brain with the highest concentrations of

glutamate or other excitatory amino acid receptors (primarily

located in gray matter) are more susceptible to excitotoxic injury

that occurs as a result of hypoxia-ischemia.

(b) the areas of the brain with the greatest energy demands

become energy depleted most rapidly during hypoxia-ischemia,

and are therefore injured early on.

(c) because of delayed cell death from apoptosis, some injuries

may not be evident until days after the initial insult has occurred

HIE

In any given patient, the sites in the brain that tend to be

most vulnerable to hypoxic injury will be determined largely

by the maturity of the brain, which, in turn, is a function of

patient age and, in infants, gestational age at birth. This is

why HII in the perinatal period (up to 1 month of age) differs

from HII in adults or even in older infants.

HIE

The severity of a hypoxic-ischemic insult also plays an

important role in determining the distribution of injuries in the

brain.

Duration of insult also seems to be a key determinant of the

pattern of injury in HII,

TERM NEONATE

HII in term neonates is associated with antepartum risk factors alone

(including maternal hypotension, infertility treatment, multiple

gestation, prenatal infection, and thyroid disease) or antepartum

factors in combination with intrapartum factors.

Intrapartum factors alone (including forceps delivery, breech

extraction, umbilical cord prolapse, abruptio placentae, tight nuchal

cord, and maternal fever) are responsible for a small minority of

cases of HII.

SEVERE ASPHYXIA

Severe asphyxial events in term neonates result in a primarily central

pattern of injury involving the deep gray matter (putamina,

ventrolateral thalami, hippocampi, dorsal brainstem, and lateral

geniculate nuclei) and occasionally the perirolandic cortex.

These areas of the brain are actively myelinating (an energy-

intensive process) or contain the highest concentrations of NMDA

receptors at term and are, therefore, the most susceptible to neonatal

HII

USG

Early US findings include a global increase in cerebral echogenicity

and obliteration of the cerebrospinal fluid (CSF)–containing spaces,

suggesting diffuse cerebral edema.

Increased echogenicity in the basal ganglia, thalami, and brainstem

can also be seen in the 1st week but is more readily apparent after 7

days.

USG

Late findings include prominence of the ventricles and extraaxial

CSF-containing spaces, likely due to atrophy.

The presence of diminished resistive indexes (<60) in the anterior

and middle cerebral arteries has been associated with a poor clinical

outcome, even in the absence of other US abnormalities.

MRI

Diffusion-weighted imaging is sensitive for the detection of

injury in the first 24 hours, during which time conventional T1-

and T2-weighted images may appear normal.

Diffusion-weighted images will demonstrate increased signal

intensity in the region of the ventrolateral thalami and basal

ganglia (particularly the posterior putamina), in the

perirolandic regions, and along the corticospinal tracts

MRI

It should be noted that, although diffusion-weighted images

seemingly improve and appear relatively normal by the end

of the 1st week, this finding does not imply that there has

been improvement or reversal of underlying disease. Hence,

we use the term pseudonormalization.

MRI

Conventional T1- and T2-weighted MR images obtained on day 1 are

frequently normal and are therefore less useful than diffusion-

weighted images obtained for the diagnosis of HII in the acute

setting. By day 2, injured areas may demonstrate hyperintensity on

both T1- and T2-weighted images.

In the chronic stage of injury, atrophy of the injured structures will be

seen along with T2 hyperintensity, particularly in the ventrolateral

thalami, posterior putamina, and corticospinal tracts.

Severe neonatal HII in a 7-day-old term infant.

Axial T1-weighted MR image obtained at the level of the basal ganglia shows

increased signal intensity in the lentiform nuclei (*) and ventrolateral thalami (arrows).

T2-weighted MR image shows decreased signal intensity in the posterior aspects of

the putamina (arrowheads) and ventrolateral thalami (arrows)

Diffusion-weighted MR image shows a relative lack of hyperintensity in the

locations cited earlier, findings that represent pseudonormalization. Only the left

globus pallidus shows high signal intensity. Corresponding ADC map shows

hypointensity

Severe neonatal HII in a 5-day-old term infant who suffered profound birth asphyxia.

(a, b) Axial T1-weighted MR images show hyperintensity in the ventrolateral thalami

(arrowheads in a), basal ganglia (arrows in a), and perirolandic cortex (arrows inb)

Axial T2-weighted MR images obtained approximately 7 months later show diffuse

atrophy as well as hyperintensity (gliosis) in the ventrolateral thalami (arrowheads

in c), posterior putamina (arrows in c), and perirolandic regions (arrows in d).

PARTIAL ASPHYXIA

The brainstem, cerebellum, and deep gray matter structures are

generally spared from injury in mild to moderate hypoxic-ischemic

insults, since autoregulatory mechanisms are able to maintain

perfusion to these areas of the brain.

In neonates, moderate insults of short duration cause little or no

injury to the brain; however, more prolonged insults result in injury to

the intervascular boundary (watershed) zones, which are relatively

hypoperfused as a result of this shunting.

MRI

Diffusion-weighted images are the earliest to change, usually within

the first 24 hours following injury, and typically demonstrate cortical

and subcortical white matter restriction, most pronounced in the

parasagittal watershed territories.

By day 2, T2-weighted images will often demonstrate cortical swelling

with loss of differentiation between gray matter and white matter and

hyperintensity in the cortex and subcortical white matter,

predominantly in the parasagittal watershed zones but occasionally

involving the hemispheres diffusely.

Partial neonatal HII in a 2-day-old term infant who experienced seizures

shortly after birth. (a, b)Axial T1-weighted (a) and T2-weighted (b) MR images

appear essentially normal.

Diffusion-weighted MR image (c) and corresponding ADC map (d) show

restricted diffusion in the cortex and subcortical white matter in a parasagittal

watershed distribution.

PRETERM NEONATE

HII is more common in preterm neonates than in term

neonates.

HII in preterm infants, particularly those of very low birth

weight, is difficult to diagnose clinically early on because

signs may be lacking or mistaken to result from

developmental immaturity.

Profound hypoxic-ischemic events in preterm neonates

manifest predominantly as damage to the deep gray matter

structures and brainstem.

Events of mild to moderate severity in this population

typically manifest as either germinal matrix–intraventricular

hemorrhages or periventricular white matter damage (also

referred to as periventricular leukomalacia.

SEVERE ASPHYXIA

Injury to the thalami, basal ganglia, hippocampi, cerebellum, and

corticospinal tracts can be seen, with the thalami, anterior vermis,

and dorsal brainstem being most frequently involved.

Although basal ganglia injury is frequently encountered in this group,

involvement of these structures is less severe compared with

involvement of the thalami, particularly among neonates born at less

than 32 weeks gestation.

Germinal matrix hemorrhages and periventricular white matter injury

may also be seen.

USG

US of the brain in preterm neonates with HII may

demonstrate increased echogenicity in the thalami by 48–72

hours following an insult but may also be normal, particularly

in the first 2 days.

MRI

Conventional MR imaging performed within the 1st day after injury

may be normal or show only subtle abnormalities.

Diffusion abnormalities are usually evident in the thalami within 24

hours .

After 2 days, T2 prolongation can be seen in the thalami and basal

ganglia.

MRI

By the 3rd day following injury, T1 shortening (hyperintense)

will be seen in the injured areas.

Diffusion-weighted abnormalities are most apparent around

days 3–5 following insult and subsequently begin to

pseudonormalize . T2 shortening (hypointense) develops in

the injured areas at approximately 7 days, and T1 shortening

persists into the chronic stage.

Diffusion-weighted MR image and corresponding ADC map obtained the

following day(b) show restricted diffusion in the ventrolateral thalami

MILD TO MODERATE

ASPHYXIA

The overall prevalence of intraventricular hemorrhage in

preterm neonates weighing less than 2000 g is approximately

25%, and in the majority of cases this bleeding occurs within

the first 24 hours of life.

Prevalence is inversely related to gestational age and weight

at birth. The majority of intraventricular hemorrhages in

preterm neonates are associated with germinal matrix

hemorrhages.

Sonographic grading system proposed by Burstein and Papile et.al:

grade I

restricted to subependymal region / germinal matrix which is seen in the

caudothalamic groove

grade II

extension into normal sized ventricles and typically filling less than 50% of the

volume of the ventricle

grade III

extension into dilated ventricles

grade IV

grade III with parenchymal haemorrhage

90% mortality.

It should be noted that it is now thought that grade IV bleeds are not simply

extensions of germinal matrix haemorrhage into adjacent brain, but rather

represent sequelae of venous infarction

Grading of neonatal intracranial haemorrhage

In grade I hemorrhage, small subependymal hemorrhages are seen as

hyperechoic foci in the region of the caudothalamic grooves

Grade II hemorrhage is seen in the caudothalamic grooves (arrows) with

blood extending into the lateral ventricles

In grade III hemorrhage , intraventricular extension of hemorrhage is again seen,

in this case involving both lateral ventricles (arrowheads) and the third ventricle

(arrow). Marked ventriculomegaly is also noted

In grade IV hemorrhage , there is hemorrhage originating in the

periventricular white matter (arrow) and extending into the ventricles.

Cerebellar hemorrhages have also been reported at autopsy in

up to 25% of preterm infants with very low birth weight.

It has been hypothesized that these hemorrhages are in fact

germinal matrix hemorrhages arising from germinal zones

known to exist within the external granule cell layer of the

cerebellar hemispheres.

These hemorrhages are usually lentiform or

crescentic and are located peripherally in the dorsal

aspects of the cerebellar hemispheres.

Coronal and sagittal US images obtained in the 1st week of life demonstrate an

area of echogenicity (arrow) in the left cerebellar hemisphere, a finding that is

compatible with hemorrhage.

On a coronal US image obtained approximately 2 weeks later, the area of

interest is hypoechoic (arrow), a finding that suggests liquefaction of the

hemorrhage.

Periventricular leukomalacia (PVL), also referred to as white

matter injury of prematurity, is a common occurrence among

premature infants.

PVL is most frequently observed adjacent to the trigones of the

lateral ventricles and adjacent to the foramina of Monro.

Initially, there is necrosis, often progressing to cavitation and

the development of porencephalic cysts

Four stages of PVL have been described at US . Initially, there is

congestion, which manifests as globular areas of increased

echogenicity (sometimes referred to as “flares”) in the

periventricular regions in the first 48 hours.

These findings are followed by a transient period of relative

normalization, usually by the 2nd–4th weeks of life.

Periventricular cyst development then occurs at approximately

3–6 weeks of life.

Finally, by 6 months of age, end-stage PVL results, with

resolution of cysts and associated ventricular enlargement

Coronal head US image obtained in the 1st week of life shows increased

echogenicity in the periventricular white matter (arrows)

Follow-up US image obtained 2 months later shows development of

cystic changes in these regions and dilatation of the adjacent lateral

ventricles

MRI

At MR imaging, early white matter injury will manifest as

periventricular foci of T1 shortening/hyperintensity (without

corresponding T2 shortening/hypointensity) within larger areas of T2

prolongation.

These foci are usually evident by 3–4 days, subsequently giving way

to mild T2 shortening at 6–7 days .

In contrast, hemorrhage (reported to be present in 64% of cases of

PVL) initially manifests with much lower signal intensity on T2-

weighted images.

Axial T1-weighted and T2-weighted MR images obtained on day 4 of life

demonstrate T1 hypointensity and T2 hyperintensity in the periventricular white

matter. Note the punctate foci of high signal intensity on the T1-weighted image

End stage PVL - Axial fluid-attenuated inversion recovery MR images

demonstrate increased signal intensity and a few tiny cysts in the

immediate periventricular white matter.

There is enlargement of the atria of the lateral ventricles with a decrease

in volume of the adjacent white matter, and the walls of the lateral

ventricles have a wavy appearance.

POSTNATAL INFANTS &

YOUNG CHILDREN

Hypoxic-ischemic injuries in infants and young children are

usually the result of drowning, choking, or non accidental

trauma.

As myelination nears completion by about 2 years of age,

injuries similar to the pattern seen in adults begin to appear.

SEVERE ASPHYXIA

Severe insults to infants between 1 and 2 years of age result

in injuries to the corpora striata, lateral geniculate nuclei,

hippocampi, and cerebral cortex (particularly the anterior

frontal and parieto-occipital cortex), with relative sparing of

the thalami and perirolandic cortex.

Injuries occurring after the immediate perinatal period but

before 1 year of age can demonstrate features of both birth

asphyxia and later infantile asphyxia, with involvement of the

basal ganglia (predominantly posteriorly), lateral thalami, and

dorsal midbrain, as well as cortical injury.

CT

Early CT performed within 24 hours of an insult may be negative or may demonstrate only subtle hypoattenuation of the deep gray matter structures .

Subsequent CT will demonstrate diffuse basal ganglia abnormalities along with diffuse cerebral edema, manifesting as cortical hypoattenuation, loss of normal “gray-white” differentiation, and cisternal and sulcal effacement.

There may be relative sparing of the perirolandic regions . Hemorrhagic infarctions of the basal ganglia may be evident by 4–6 days .

Imaging in the chronic phase will demonstrate diffuse atrophy with sulcal and ventricular enlargement

CT

Within the first 24 hours, a small number of these patients may

demonstrate the “reversal sign,” in which there is reversal in the

normal CT attenuation of gray matter and white matter.

Another well-known CT sign of severe HII is the “white cerebellum

sign” , which has been described in at least one study as a

component of the reversal sign and in which there is diffuse edema

and hypoattenuation of the cerebral hemispheres with sparing of

the cerebellum and brainstem, resulting in apparent high

attenuation of the cerebellum and brainstem relative to the cerebral

hemispheres.

Unenhanced CT scan shows diffuse cortical swelling and hyperattenuation in

the white matter relative to areas of preserved cortex, a finding that is referred to

as the reversal sign and generally portends a poor prognosis. A small amount of

extraaxial hemorrhage adjacent to the left frontal lobe is also seen.

Unenhanced CT scan demonstrates the white cerebellum sign. The

cerebellar hemispheres (*) are hyperattenuating relative to the supratentorial

structures, which are hypoattenuating due to edema.

Unenhanced CT scan obtained at the level of the basal ganglia after

cardiopulmonary arrest that lasted 30 minutes is essentially unremarkable

On an unenhanced CT scan, the cerebellum appears slightly hyperattenuating

relative to the rest of the brain

Diffusion-weighted and T2-weighted MR images obtained 4 days later show

high signal intensity with corresponding T2 abnormalities in the caudate nuclei

(white arrows), lentiform nuclei (black arrows), and occipital lobes (*

MRI

MR imaging is frequently performed in children with HII.

Diffusion-weighted images will usually be abnormal within the

first 12–24 hours, initially demonstrating bright signal

intensity in the posterolateral lentiform nuclei ; thalamic

involvement (when present) will usually involve the

ventrolateral nuclei.

Over the next 48 hours, there is typically significant

progression of involvement to include the remainder of the

basal ganglia and the cortex

MRI

Conventional T1- and T2-weighted images obtained in the

first 24 hours are often normal and may appear so for up to 2

days.

By 48 hours, T2-weighted images will usually demonstrate

diffuse basal ganglia and cortical signal intensity abnormality

MILD TO MODERATE ASPHYXIA

As in term neonates, milder anoxic events in older infants will

generally result in watershed zone injuries involving the

cortex and subcortical white matter.

White matter lesions are more common in children under 1

year of age. Relative sparing of the periventricular white

matter will be seen.

Unenhanced head CT scan shows bilateral cortical and subcortical

hypoattenuation in the parasagittal watershed regions

Diffusion-weighted MR image obtained at the same level shows corresponding

high-signal-intensity areas compatible with watershed infarcts.

OLDER CHILDREN & ADULTS

HII in adults is more often a result of cardiac arrest or

cerebrovascular disease, with secondary hypoxemia.

Drowning and asphyxiation remain common causes of HII in

older children.

Mild to moderate global ischemic insults to the brain usually

result in watershed zone infarcts.

Severe HII in this population primarily affects the gray matter

structures: the basal ganglia, thalami, cerebral cortex (in

particular the sensorimotor and visual cortices, although

involvement is often diffuse), cerebellum, and hippocampi

CT

In older patients, CT is generally the initial imaging study

performed when brain injury is suspected.

CT findings include diffuse edema with effacement of the

CSF-containing spaces, decreased cortical gray matter

attenuation with loss of normal gray-white differentiation, and

decreased bilateral basal ganglia attenuation.

As in young children, the reversal sign and the white

cerebellum sign may be seen in adults.

MRI

Diffusion-weighted MR imaging is the earliest imaging

modality to become positive, usually within the first few hours

after a hypoxic-ischemic event.

During the first 24 hours, diffusion-weighted imaging may

demonstrate increased signal intensity in the cerebellar

hemispheres, basal ganglia, or cerebral cortex (in particular,

the perirolandic and occipital cortices) .

The thalami, brainstem, or hippocampi may also be involved

MRI As in younger patients, conventional T1- and T2-weighted images are

often normal or demonstrate only very subtle abnormalities.

In the early subacute period (24 hours–2 weeks), conventional T2-weighted images typically become positive and demonstrate increased signal intensity and swelling of the injured gray matter structures, although these findings may be subtle. As mentioned earlier, diffusion-weighted imaging abnormalities usually pseudonormalize by the end of the 1st week .

Gray matter signal intensity abnormalities at conventional MR imaging may persist into the end of the 2nd week.

In the chronic stage, T2-weighted images may demonstrate some residual hyperintensity in the basal ganglia, and T1-weighted images may show cortical necrosis , which is seen as areas of high signal intensity in the cortex

Axial T2-weighted and diffusion-weighted MR images show diffuse white matter

hyperintensity. On the corresponding ADC map, the white matter is hypointense

MR SPECTROSCOPY

MR spectroscopy is perhaps more sensitive to injury and more

indicative of the severity of injury in the first 24 hours after a

hypoxic-ischemic episode, when conventional and diffusion-

weighted MR imaging may yield false-negative findings or lead

to significant underestimation of the extent of injury.

MR spectroscopy will demonstrate substantial lactate elevation

(appearing as a doublet centered in the deep gray nuclei, parieto-

occipital region, or white matter of the parasagittal watershed

zones by as early as 2–8 hours .

A glutamine-glutamate peak may also be detected , probably

reflecting the release of glutamate that occurs in HII.

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